Primary or acquired drug resistance is well recognized as a common cause of treatment failure of patients with cancer. From a rheumatoid arthritis (RA) perspective, the issue of resistance to anti-rheumatic drugs (e.g. disease-modifying anti-rheumatic drugs [DMARDs]) has not received much attention. A possible mechanism of drug resistance is overexpression of multidrug resistance (MDR)-related proteins. The objective of this study was to identify whether various MDR proteins are expressed on macrophages as potential target cells for DMARDs.
Monocyte-derived macrophages (MDM) were obtained from 15 RA patients (median age: 56 years, 13 females/two males) and eight healthy controls (median age: 51 years, four females/four males). Monocytes were isolated from peripheral blood mononuclear cells and differentiated into macrophages in the presence of monocyte-colony stimulating factor. Cytospins of MDMs were prepared for immunohistological analysis of the MDR-related proteins: P-glycoprotein, multidrug resistance associated protein (MRP) 1, MRP4, MRP5, breast cancer resistance protein (BCRP) and lung resistance protein (LRP). Staining intensities were scored as follows: (0), negative; (1), weakly positive; (2), positive; (3), strongly positive. The total score is depicted as the summation of percentiles of cells with intensities 0–3.
MDMs of healthy controls and of RA patients stained strongly positive for macrophage markers CD68 and 3A5. Except for MRP4, MDR protein expression was observed both in MDMs of healthy controls and RA patients. Results are shown as the median score with ranges (in parentheses) for MDR expression and a statistical evaluation (Mann–Whitney U test) for differential expression (Table 1).
Table 1. Multidrug resistance (MDR) protein expression in monocyte-derived macrophages from rheumatoid arthritis patients and healthy controls as median scores (ranges)
MDR proteins, known to be involved in conferring drug resistance, are expressed on macrophages of RA patients. Beyond this, there seems to be a trend for a higher expression of MDR proteins on MDM from RA patients compared with healthy controls. Further studies are warranted to assess whether MDR is a clinically relevant issue in daily treatment of RA patients.
This study is supported by the Dutch Arthritis Association (Grant NRF-03-I-40).